title: The preferential dopamine D3 receptor agonist cis-8-OH-PBZI induces limbic Fos expression in rat brain.
abstract: The affinity, selectivity and agonistic properties of a constrained dopaminergic compound, the benz[e]indole cis-8-hydroxy-3-(n-propyl)1,2,3a.4,5,9b-hexahydro-1H-benz[e]indole (cis-8-OH-PBZI), for the dopamine D3 receptor were evaluated in competition binding experiments with cloned human dopamine receptor subtypes and, to further extend its profile, in in vitro radioligand binding assays. The Ki value measured for competition binding of this compound to the dopamine D3 receptor was 27.4+/-3.1 nM; this was 775-fold, 550-fold, 90-fold and 10-fold higher affinity than that measured at dopamine D1A, D5, D2s and D4 receptors, respectively. Evidence of dopamine receptor activation by cis-8-OH-PBZI was obtained by measuring dose-dependent increases in extracellular acidification rates and decreases in cAMP synthesis. In vivo, cis-8-OH-PBZI potently induced Fos protein immunoreactivity in the rat medial prefrontal cortex and shell region of the nucleus accumbens, but only marginally in the motor dorsolateral striatum, indicating a selective limbic site of action. In conclusion, the present data identify cis-8-OH-PBZI as having preference for the dopamine D3 receptor in vitro, and as having dopamine agonist activity and limbic sites of action in vivo.
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Bagsvaerd, Denmark.
authors.forename: M A
authors.initials: MA
authors.lastname: Scheideler
authors.forename: J
authors.initials: J
authors.lastname: Martin
authors.forename: R
authors.initials: R
authors.lastname: Hohlweg
authors.forename: J S
authors.initials: JS
authors.lastname: Rasmussen
authors.forename: L
authors.initials: L
authors.lastname: Naerum
authors.forename: T S
authors.initials: TS
authors.lastname: Ludvigsen
authors.forename: P J
authors.initials: PJ
authors.lastname: Larsen
authors.forename: N
authors.initials: N
authors.lastname: Korsgaard
authors.forename: A M
authors.initials: AM
authors.lastname: Crider
authors.forename: D
authors.initials: D
authors.lastname: Ghosh
authors.forename: S F
authors.initials: SF
authors.lastname: Cruse
authors.forename: A
authors.initials: A
authors.lastname: Fink-Jensen
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000187:drug effects; D050637:Receptors, Dopamine D3; D015398:Signal Transduction; D014793:Visual Cortex / Q000187:drug effects / Q000378:metabolism
chemical_list: C111033:8-hydroxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-1H-benz(e)indole; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D007211:Indoles; D016760:Proto-Oncogene Proteins c-fos; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3